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Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral CDAi in Patients With MDS

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ClinicalTrials.gov Identifier: NCT02103478
Recruitment Status : Completed
First Posted : April 4, 2014
Last Update Posted : January 9, 2020
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE March 20, 2014
First Posted Date  ICMJE April 4, 2014
Last Update Posted Date January 9, 2020
Study Start Date  ICMJE May 2014
Actual Primary Completion Date June 5, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 5, 2016)
  • Pharmacokinetics: plasma decitabine after oral decitabine and E7727 area under the plasma concentration versus time curve (AUC) by cohort. [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Plasma Pharmacokinetics. Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) area under the plasma concentration versus time curve (AUC).
  • Incidence of Dose limiting toxicities by cohort [ Time Frame: Phase 1 in Cycle 1 (28 days) ]
    Protocol specified grade 3 and 4 adverse events
  • Pharmacodynamics: Maximum %LINE-1 demethylation of ASTX727 compared to 20mg/m2 IV decitabine [ Time Frame: (Phase 1 and 2) Days 1,8,15 and 22 for Cycles 1 and 2. Day 1 for cycles 3 and above. ]
    Long interspread nuclear element-1 (LINE-1 or L1) sequences are highly repeated human retrotransposon sequences and constitute about 17% of the human genome. They are usually heavily methylated and their demethylation is a reliable surrogate for global genomic demethylation. Peripheral blood will be tested for DNA methylation.
  • Overall Response Rate [ Time Frame: Phase 1 and 2 through study completion ]
    Complete response rate and mCR
Original Primary Outcome Measures  ICMJE
 (submitted: April 1, 2014)
  • Dose Escalation Hematology testing [ Time Frame: Hematology daily during the first week and then weekly for an average of courses (approximately 6 months) ]
    Complete blood count with differential
  • Dose Escalation; Number of subjects with adverse events and the type of adverse events [ Time Frame: At each visit (daily in week 1 of course 1) then weekly through course 6 (an average of 6 months) ]
    Type of adverse event includes severity and causality
  • Dose Escalation; Number of subjects with changes to physical examinations [ Time Frame: Assessed at the end of course 1 in dose escalation to determine the next cohort/stage of the study then as needed in the study through course 6 (an average of 6 months) ]
    Symptom directed physical examinations will be performed at each visit
  • Dose Confirmation Clinical Laboratory testing [ Time Frame: Hematology daily during the first week and then weekly through course 6; serum chemistry weekly through course 6 (an average of 6 months) ]
    Complete blood count and differential, serum chemistry
  • Dose Confirmation; Number of subjects with adverse events and the type of adverse events [ Time Frame: At each visit (daily in week 1 of course 1 and weekly through course 2 then each course then weekly through course 6) (an average of 6 months) ]
    Type of adverse event includes severity and causality
  • Dose Confirmation; Number of subjects with changes to physical examinations [ Time Frame: Change from baseline to course 6 or last visit if prior to course 6 (an average of 6 months) ]
    Symptom directed physical examinations will be performed at each visit
  • Dose Escalation Serum Chemistry testing [ Time Frame: Weekly through course 6 (an average of 6 months) ]
    Serum Chemistry, electrolytes, liver enzymes, BUN, creatinine
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2016)
  • Pharmacokinetics: area under the plasma concentration versus time curve (AUC) of oral decitabine, E7727 and E7727-epimer [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of area under the plasma concentration versus time curve (AUC)during dose escalation and dose confirmation-randomization.
  • Pharmacodynamics: Mean maximum % demethylation of the LINE-1 elements in peripheral blood will be reported by cohort [ Time Frame: (Phase 1 and 2) Days 1,8,15 and 22 for Cycles 1 and 2. Day 1 for cycles 3 and above. ]
    Long interspread nuclear element-1 (LINE-1 or L1) sequences are highly repeated human retrotransposon sequences and constitute about 17% of the human genome. They are usually heavily methylated and their demethylation is a reliable surrogate for global genomic demethylation. Peripheral blood will be tested for DNA methylation.
  • Number and proportion of subjects with adverse events by type and grade [ Time Frame: Phase 1 and 2 , through study completion, an average of one year ]
    Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
  • Pharmacokinetics: Maximum Plasma Concentration (Cmax) of oral decitabine, E7727 and E7727-epimer [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of Maximum Plasma Concentration (Cmax) during dose escalation and dose confirmation-randomization.
  • Pharmacokinetics: Minimum Plasma Concentration (Cmin) of oral decitabine, E7727 and E7727-epimer [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of Minimum Plasma Concentration (Cmin) during dose escalation and dose confirmation-randomization.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 1, 2014)
  • Dose Escalation and Dose Confirmation-Randomization; AUC, Cmax, Cmin [ Time Frame: Courses 1 and 2 (approximately 2 months) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters ( AUC, Cmax, Cmin) during dose escalation and dose confirmation-randomization.
  • Response to treatment [ Time Frame: Prior to every odd course (1, 3, 7) until course 7 (an average of 4 times over 6 months) ]
    Treatment response will be assessed through analysis of peripheral blood and bone marrow aspirations/biopsies prior to the start of course 3, 5 and 7.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral CDAi in Patients With MDS
Official Title  ICMJE A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine in Subjects With Myelodysplastic Syndromes (MDS)
Brief Summary This 2-stage, open-label study will evaluate safety and pharmacokinetics of ASTX727, as well as determine the dose for the study's second stage. In the second stage the selected dose will be confirmed and evaluated for clinical activity, including response rate.
Detailed Description Dose levels for the study's second stage will be based on safety and pharmacokinetics.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndrome
  • MDS
Intervention  ICMJE
  • Drug: ASTX727 Dose Escalation
    Oral investigational product and approved IV decitabine
    Other Names:
    • E7727
    • oral decitabine
    • IV decitabine
  • Drug: ASTX727 Dose Confirmation
    Randomization cross over design for courses 1 and 2
    Other Names:
    • ASTX727 oral (combination of oral E7727 and oral decitabine)
    • IV decitabine
Study Arms  ICMJE
  • Experimental: Phase 1 ASTX727 Dose Escalation
    ASTX727 is given by mouth daily X 5 consecutive days. Dosing details will vary in the first 3 courses of therapy for pharmacokinetic measurements. Based on safety and pharmacokinetic results the dose will be modified for subsequent cohorts. Dose escalation will continue until target pharmacokinetics are achieved or until a safe dose is exceeded. This dose will be carried forward into Phase 2.
    Intervention: Drug: ASTX727 Dose Escalation
  • Active Comparator: Phase 2 ASTX727 Dose Confirmation
    Subjects will compare one cycle of daily x 5 IV decitabine vs. one cycle of daily x 5 oral decitabine and E7727 for PK and PD. They will be randomized 1:1 as to the order the cycles are administered. In cycle 3 or greater the oral combination will be administered.
    Intervention: Drug: ASTX727 Dose Confirmation
Publications * Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019 Apr;6(4):e194-e203. doi: 10.1016/S2352-3026(19)30030-4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 25, 2017)
113
Original Estimated Enrollment  ICMJE
 (submitted: April 1, 2014)
150
Actual Study Completion Date  ICMJE December 4, 2019
Actual Primary Completion Date June 5, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • IPSS low, intermediate -1, intermediate-2, or high risk MDS (including CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
  • ECOG 0 to 2
  • No major surgery within 2 weeks of starting study treatment
  • No cytotoxic chemotherapy within 2 weeks of starting study treatment
  • Able to swallow pills

Exclusion Criteria:

  • Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only)
  • Treatment with investigational therapy within 2 weeks of study treatment
  • Uncontrolled medical disease(s) or active, uncontrolled infection
  • Diagnosed with AML
  • Active uncontrolled gastric or duodenal ulcer
  • Known history of HIV or hepatitis C or B
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02103478
Other Study ID Numbers  ICMJE ASTX727-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Astex Pharmaceuticals, Inc.
Study Sponsor  ICMJE Astex Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mohammad Azab, MD Astex Pharmaceuticals, Inc.
Study Chair: James Lowder, MD Astex Pharmaceuticals, Inc.
PRS Account Astex Pharmaceuticals, Inc.
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP